ArticleStem cells (Dayton, Ohio)2014
The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors.
Article in Stem cells (Dayton, Ohio), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 67 papers, 1 of them a synthesis that pooled it.
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Who cites it
67 citing papers in PubMed, 1 synthesis or guideline pooled it, 89 citations in OpenAlex.
- The effect of BIM deletion polymorphism on intrinsic resistance and clinical outcome of cancer patient with kinase inhibitor therapy.Scientific reports · 2015Pooled it
- Oxidative Phosphorylation and Fatty Acid Oxidation Are Central to Mitochondrial Metabolism Rewiring in CML Stem/Progenitor Cell Survival.Pathophysiology : the official journal of the International Society for Pathophysiology · 2026Review
- CanInternational journal of molecular sciences · 2026Article
- Understanding drug resistance in chronic myeloid leukemia through the lens of leukemic stem cell states: insights from single-cell analyses.Haematologica · 2026Review
- Decoding Leukemic Stem Cells in AML: From Identification to Targeted Eradication.Diseases (Basel, Switzerland) · 2026Review
- Lung adenocarcinoma surfaceome remodeling with EGFR inhibitors uncovers placental alkaline phosphatase as a target for combination therapy.Cell reports. Medicine · 2025Article
- The dual role of autophagy in cancer stem cells: implications for tumor progression and therapy resistance.Journal of translational medicine · 2025Review
- BCAT1 contributes to the development of TKI-resistant CML.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Autophagy crosstalk with the immune microenvironment in chronic myeloid leukemia and serves as a biomarker for diagnosis and progression.Frontiers in immunology · 2025Article
- Identified senescence endotypes in aged cartilage are reflected in the blood metabolome.GeroScience · 2024Article
- Dormant cancer cells and polyploid giant cancer cells: The roots of cancer recurrence and metastasis.Clinical and translational medicine · 2024Review
- The discrete roles of individual FOXO transcription factor family members in B-cell malignancies.Frontiers in immunology · 2023Review
- Decreased FOXO1 Expression Is Correlated with Poor Prognosis in Myelodysplastic Syndromes.Current oncology (Toronto, Ont.) · 2022Article
- Summarizing internal dynamics boosts differential analysis and functional interpretation of super enhancers.Nucleic acids research · 2022Article
- BCR-ABL1 Tyrosine Kinase Complex Signaling Transduction: Challenges to Overcome Resistance in Chronic Myeloid Leukemia.Pharmaceutics · 2022Review
- Chronic myeloid leukemia stem cells: targeting therapeutic implications.Stem cell research & therapy · 2021Review
- Shedding Light on Targeting Chronic Myeloid Leukemia Stem Cells.Journal of clinical medicine · 2021Review
- Review
- New routes to eradicating chronic myelogenous leukemia stem cells by targeting metabolism.International journal of hematology · 2021Review
- Cancer non-stem cells as a potent regulator of tumor microenvironment: a lesson from chronic myeloid leukemia.Molecular biomedicine · 2021Review
7 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Chronic myeloid leukemia (CML) is initiated and maintained by the tyrosine kinase BCR-ABL which activates a number of signal transduction pathways, including PI3K/AKT signaling and consequently inactivates FOXO transcription factors. ABL-specific tyrosine kinase inhibitors (TKIs) induce minimal apoptosis in CML progenitor cells, yet exert potent antiproliferative effects, through as yet poorly understood mechanisms. Here, we demonstrate that in CD34+ CML cells, FOXO1 and 3a are inactivated and relocalized to the cytoplasm by BCR-ABL activity. TKIs caused a decrease in phosphorylation of FOXOs, leading to their relocalization from cytoplasm (inactive) to nucleus (active), where they modulated the expression of key FOXO target genes, such as Cyclin D1, ATM, CDKN1C, and BCL6 and induced G1 arrest. Activation of FOXO1 and 3a and a decreased expression of their target gene Cyclin D1 were also observed after 6 days of in vivo treatment with dasatinib in a CML transgenic mouse model. The over-expression of FOXO3a in CML cells combined with TKIs to reduce proliferation, with similar results seen for inhibitors of PI3K/AKT/mTOR signaling. While stable expression of an active FOXO3a mutant induced a similar level of quiescence to TKIs alone, shRNA-mediated knockdown of FOXO3a drove CML cells into cell cycle and potentiated TKI-induced apoptosis. These data demonstrate that TKI-induced G1 arrest in CML cells is mediated through inhibition of the PI3K/AKT pathway and reactivation of FOXOs. This enhanced understanding of TKI activity and induced progenitor cell quiescence suggests that new therapeutic strategies for CML should focus on manipulation of this signaling network.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.